1. Field of the Art
This invention relates to an enhancer of anti-tumor effect.
In the art of treatment of tumors, there have been many developments from various aspects. In radiotherapy, as a branch of the development, there have also been attempts to improve the results of therapy. As one method, it is proposed to improve geometrical distribution by use of such methods as radiation of accelerated heavy ion particles or .pi. mesons. Another approach now under the development is to enhance selectively the sensitivity of tumor cells under hypoxic conditions, which are most resistant to radiotherapy among tumors, by utilizing a hypoxic cell sensitizer. Alternatively, combination treatments incorporating a method utilizing other anti-tumor factors, such as hyperthermia or chemotherapy have been attempted.
However, in the method for improvement of geometrical dose distribution, it is required to use enormous funds for installation of an accelerator and auxiliary equipment necessary for practicing the method as well as a large personnel requirements, including expert engineers and physicians. Other methods also involve drawbacks such as great damage to normal cells. For example, misonidazole, which is a hypoxic cell sensitizer, has neurotoxicity, and hence it is difficult to administer it in a large quantity, whereby no great radiosensitizing effect can be expected at concentrations available in clinical use, its effect being small in a low dose range (less than 1000 rad) as employed in a routine therapy.
In view of the fact that the tumor cells with radioresistance under hypoxic conditions are at a quiescent stage, I have investigated the possibility of radiosensitization by inhibiting potentially lethal damage repair (hereinafter referred to as "PLDR"), which is especially marked in quiescent cells. During the course of this investigation, 3'-deoxyadenosine (cordycepin, herein referred to as "3'-dAdo") was confirmed to have a PLDR-inhibiting ability. However, 3'-dAdo is readily inactivated by adenosinedeaminase in bodies. I found that the PLDR-inhibiting ability of 3'-dAdo can be strengthened and prolonged by using it in combination with 2'-deoxycoformycin, which is an inhibitor against adenosinedeaminase. However, there is also a report that 2'-deoxycoformycin may cause damage to the immune systems, and 3'-dAdo is also known to have various side effects. Thus, it would be very desirable to have a radiosensitizing substance which is more stable, lower in toxicity, and more effective than 3'-dAdo.
On the other hand, in the field of chemotherapy of tumors, multiple anti-tumor agents have been combined to be used for the following purposes and effects:
(1) By using in combination a number of different agents selected from those of alkylating agents, antimetabolites, antibiotics and alkaloids, which show mutually no cross resistance and are different in mechanism of action, the anti-tumor effect can be enhanced additively or synergistically against tumors which are composed of a mixture of tumor cells different in sensitivity to various agents.
(2) By using in combination anti-tumor agents different in the way they attack tumor cells which are proliferating at random, various stages in the cell cycle of tumor cells can be widely attacked to ensure complete killing of tumor cells.
(3) By using not only agents different in mechanism of action but also those having relatively similar mechanisms of action, a synergistic effect can be expected. For example, by using in combination a number of agents which are blocking a series of steps participating in DNA synthesis, a strong synergistic effect can be exhibited.
(4) Each anti-tumor agent has its specific side effect. Thus, by using in combination a number of agents with different side effects each in a dosage less than the limit above which side effects appear, the anti-tumor effect can be expected to be increased additively or synergistically while the side effects are dispersed.
By such a multi-agent combination treatment, it has been made possible to obtain an effect which could not be produced by using a single anti-tumor agent. However, each of the agents used in combination in such an application is an anti-tumor agent which can be independently used.
There have also been various attempts to use in combination with an anti-tumor agent a compound which does not per se have an anti-tumor effect for the purpose of strengthening the effect of the anti-tumor agent by preventing the anti-tumor agent from being inactivated in bodies. For example, it is known to use cytidine or uridine in combination with 1-.beta.-D-arabinofuranosylcytosine (hereinafter referred to as "araC"), as disclosed in Japanese Laid-Open Patent Application No. 24150/1980. It is also known to use tetrahydrouridine, which is an inhibitor against cytidinedeaminase, in combination with araC, as disclosed in Cancer Research Vol.30, p. 2166-2172, 1970. Further, there is known another method wherein 5-fluorouracil (hereinafter referred to as "5-FU") or a derivative thereof is combined with a pyrimidine compound such as, for example, uracil, cytosine, thymine, orotic acid, 5-bromouracil, 5-iodouracil, 1-acetyluracil, 1-(2-tetrahydrofuryl)-uracil, 3-benzoyluracil, 1-cyclohexycarbamoyluracil, 1-n-hexycarbamoyluracyl, uridine, 2'-deoxyuridine, 5-bromo-2'-deoxyuridine, cytidine, or 2'-deoxycytidine.
With respect to a chemotherapeutics such as Bleomycin (hereinafter referred to as "BLM") or 5-FU, PLDR is also recognized similarly as in the case of radiotherapy, as reported in the Journal of the National Cancer Institute, Vol.50, No.2, p.529-533, 1973.